EP0024181B1 - Process for the isolation of a solid salt of p-hydroxymandelic acid; some salts of p-hydroxymandelic acid - Google Patents

Process for the isolation of a solid salt of p-hydroxymandelic acid; some salts of p-hydroxymandelic acid Download PDF

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Publication number
EP0024181B1
EP0024181B1 EP80302741A EP80302741A EP0024181B1 EP 0024181 B1 EP0024181 B1 EP 0024181B1 EP 80302741 A EP80302741 A EP 80302741A EP 80302741 A EP80302741 A EP 80302741A EP 0024181 B1 EP0024181 B1 EP 0024181B1
Authority
EP
European Patent Office
Prior art keywords
salt
acid
solution
hydroxymandelic acid
hydroxymandelic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP80302741A
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German (de)
English (en)
French (fr)
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EP0024181A1 (en
Inventor
John Robert Mansfield Dales
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Beecham Group PLC
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Beecham Group PLC
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Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Priority to AT80302741T priority Critical patent/ATE3408T1/de
Publication of EP0024181A1 publication Critical patent/EP0024181A1/en
Application granted granted Critical
Publication of EP0024181B1 publication Critical patent/EP0024181B1/en
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification

Definitions

  • This invention relates to a chemical process, and in particular to a process for the isolation of a salt of p-hydroxymandelic acid. It also relates to novel salts which may be isolated by this process.
  • Salts of p-hydroxymandelic acid are valuable intermediates, for example for the preparation of p-hydroxyphenylglycine, which is useful for the manufacture of the penicillin derivative, amoxycillin.
  • Example 5b discloses in Example 5b) thereof the preparation of a solution of the sodium salt of p-hydroxymandelic acid (referred to therein as 4-hydroxyphenylglycolic acid), but this salt is not isolated.
  • Belgium Patent No. 867,287 describes a process for the manufacture of solid sodium or potassium p-hydroxymandelate monohydrate which comprises reacting by known means phenol with glyoxylic acid in the presence of, respectively, sodium or potassium hydroxide, followed by adjustment of the pH of the solution to between 5 and 7 and salting out of the desired sodium or potassium salt with respectively, a sodium or potassium salt of a simple acid.
  • the present invention provides a process for the isolation of a solid salt of p-hydroxymandelic acid, which process comprises reacting phenol with glyoxylic acid in the presence of sodium or potassium hydroxide, acidifying to a pH less than 3, extracting the resulting solution with a water-immiscible solvent to provide a solution of p-hydroxymandelic acid and precipitating the salt therefrom.
  • the reaction between phenol and glyoxylic acid may be carried out in any convenient way. Suitable conditions described in Belgium Patent No. 867,287 and also in Example 5b) of British Patent No. 1,377,243. Suitably the reaction is carried out at a temperature in the range 20°-100°C, suitably 200--600 preferably 30°-40°C. We have found that it is also preferable to adjust the dilution of the reaction solution so that the concentration of glyoxylic acid is in the range 3 to 9 % w/v, preferably 3.5 to 7%, especially 3.5 to 4.5% w/v.
  • the reaction may advantageously be carried out under nitrogen.
  • the reaction is normally carried out for a time from 3 to 8 hours, suitably about 4 hours.
  • the phenol is employed in excess.
  • concentration of phenol employed is in the range 13 to 20% w/v.
  • the sodium or potassium hydroxide is employed in a quantity related to the amount of phenol used and is conveniently employed at a concentration of from 5 to 85% w/v in the reaction mixture.
  • reaction mixture is then acidified, for example with hydrochloric or sulphuric acid, to a pH of less than 3. Preferably the pH is adjusted to 1 to 2.
  • acidified reaction mixture is then extracted with a water-immiscible solvent.
  • suitable solvents include methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, or methyl acetate, or mixtures of such solvents.
  • a preferred solvent is methyl isobutyl ketone.
  • This solvent extraction may be carried out in any conventional way, preferably by counter-current technique.
  • the required salt is precipitated from the water-immiscible solution by adding a suitable precipitating agent, depending on the particular salt.
  • suitable precipitating agents include sodium hydroxide in aqueous or alcoholic solution, or sodium ethyl hexanoate in a suitable organic solvent.
  • a solution of potassium ethyl hexanoate would be a suitable precipitating agent for preparing the potassium salt.
  • the ammonium salt may conveniently be precipitated by the addition of ammonia gas. Substituted ammonium salts can be precipitated by adding the corresponding amine itself, or a solution, thereof.
  • this invention also provides, as novel compounds solid ammonium and substituted ammonium salts of p-hydroxymandelic acid.
  • a preferred salt to precipitate in the process of this invention is the ammonium salt, because it is precipitated the most efficiently and the addition of ammonia gas is easy to control.
  • Substituted ammonium salts which may be prepared by the process of this invention include salts with primary, secondary or tertiary alkyl amines, preferably C, to C e alkylamines, for example triethylamine, sec-butylamine, t-butylamine, and cyclohexylamine.
  • the salts prepared according to the process of this invention may be converted to p-hydroxyphenylglycine by reaction with ammonia or a salt thereof as described in Belgium Patent No. 869,021.
  • a substituted ammonium salt of p-hydroxymandelic acid is employed, some N-substituted p-hydroxyphenylglycine will also be produced, and it is preferable to react the substituted ammonium salts with the correspondingly substituted amine to produce an N-substituted p-hydroxyphenylglycine.
  • the solution was adjusted to pH 7 by addition of concentrated hydrochloric acid the temperature being maintained at 35°C during the addition.
  • the mixture was extracted at 35°C with methyl isobutyl ketone (2x1.2 1) to remove excess phenol.
  • the aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid and the solution temperature reduced to 20°C.
  • the aqueous phase containing p-hydroxymandelic acid was continuously extracted with methyl isobutyl ketone in a counter-current extractor at an organic to aqueous flow rate of 3 to 2.
  • ammonia gas was passed into the stirred organic phase until no more precipitation of ammonium mandelate occurred.
  • the product was filtered off and the ammonium mandelate cake suctioned as dry as possible before drying under vacuum at 40°C.
  • Example 1 The procedure of Example 1 was repeated except that the organic phase containing p-hydroxymandelic acid was treated with a molar equivalent of sodium hydroxide as a 50% w/w aqueous solution. The caustic solution was added over one hour during which time the methyl isobutyl ketone solution was maintained at about 20°C with cooling. The precipitate of sodium p-hydroxymandelate monohydrate was filtered off and suctioned as dry as possible before drying under vacuum at 40°C.
  • Aqueous glyoxylic acid (50% w/w, 534 g) was added dropwise over 30 minutes to a stirred solution of phenol (1,014 g) and sodium hydroxide (397 g) in water (4.5 I) at 35°C. The mixture was then stirred at 35°C for 4 hours. The solution was adjusted to pH 7 with concentrated hydrochloric acid the temperature being maintained at 35°C during the addition. The solution was extracted with methyl isobutyl ketone (3x600 ml) at 35°C to remove excess phenol. The aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid and cooled to 20°C. The aqueous phase containing p-hydroxymandelic acid was continuously extracted with methyl isobutyl ketone in a counter-current extraction using an organic to aqueous flow rate of 2 to 1.
  • ammonia gas was passed into the organic phase containing the p-hydroxymandelic acid until no more precipitation of ammonium p-hydroxymandelate occurred.
  • the solid was filtered off and suctioned as dry as possible before drying under vacuum at 40°C.
  • Sodium hydroxide solution (50% w/w, ca 650 ml) was added dropwise over about one hour to a stirred mixture of phenol (1.098 kg), aqueous glyoxylic acid (50% w/w solution, 720 ml) and water (3 I) at 15°C until a pH of 10.5 had been reached.
  • the reaction mixture was then stirred and tested at 35°C for 3 hours.
  • the solution was adjusted to pH 7 with concentrated hydrochloric acid and extracted at 35°C with methyl isobutyl ketone to remove excess phenol.
  • the aqueous solution was adjusted to pH 2 with concentrated hydrochloric acid and continuously extracted in a counter-current extractor with ethyl acetate at an organic to aqueous flow rate of 1 to 1.
  • Example 5 The procedure of Example 5 was repeated except that methyl isobutyl ketone was used as the extraction solvent.
  • the triethylamine salt was prepared by treating the methyl isobutyl ketone solution with an excess of triethylamine (112 ml). The solution was stirred for 30 minutes with cooling and then left to stand at 3°C for 16 hours. The precipitate was filtered off and the cake washed with cold methyl isobutyl ketone (200 ml). The product was dried under vacuum at 40°C. The weight yield of triethylamine salt was 138.6 g.
  • Example 6 By the procedure of Example 6 the potassium salt was prepared by treating the methyl isobutyl ketone solution with an excess of a 2N solution of potassium ethyl hexanoate in methyl isobutyl ketone (400 mI). The weight yield of potassium p-hydroxymandelate was 129 g.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP80302741A 1979-08-09 1980-08-08 Process for the isolation of a solid salt of p-hydroxymandelic acid; some salts of p-hydroxymandelic acid Expired EP0024181B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT80302741T ATE3408T1 (de) 1979-08-09 1980-08-08 Verfahren zur abscheidung eines festen salzes der p-hydroxymandelsaeure; einige salze der phydroxymandels[ure.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB7927829 1979-08-09
GB7927829 1979-08-09

Publications (2)

Publication Number Publication Date
EP0024181A1 EP0024181A1 (en) 1981-02-25
EP0024181B1 true EP0024181B1 (en) 1983-05-18

Family

ID=10507098

Family Applications (1)

Application Number Title Priority Date Filing Date
EP80302741A Expired EP0024181B1 (en) 1979-08-09 1980-08-08 Process for the isolation of a solid salt of p-hydroxymandelic acid; some salts of p-hydroxymandelic acid

Country Status (8)

Country Link
US (1) US4368334A (hu)
EP (1) EP0024181B1 (hu)
JP (1) JPS56500964A (hu)
AT (1) ATE3408T1 (hu)
DE (1) DE3063330D1 (hu)
HU (1) HU182707B (hu)
NO (1) NO810291L (hu)
WO (1) WO1981000404A1 (hu)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4504678A (en) * 1981-07-20 1985-03-12 Societe Francaise Hoechst Pure crystalline racemic sodium parahydroxymandelate, process for its preparation and uses thereof
CA1303059C (en) * 1986-03-14 1992-06-09 Toshiharu Matsuda Process for producing 2,6-naphthalenedicarboxylic acid by oxidizing 2,6-diisopropylnaphthalene
FR2638740B1 (fr) * 1988-11-08 1991-07-12 Hoechst France Nouveau procede de fabrication industrielle du parahydroxymandelate de sodium
NL9202248A (nl) * 1992-12-23 1994-07-18 Univ Delft Tech Werkwijze voor het scheiden van de ortho- en para-isomeer van hydroxyamandelzuur of een zout daarvan, de volgens deze werkwijze verkregen ortho- en para-isomeer van hydroxyamandelzuur, alsmede de toepassing van de ortho-isomeer in de bereiding van EDDHA.
FR2739618B1 (fr) * 1995-10-04 1998-01-02 Hoechst France Complexe orthohydroxymandelate de sodium-phenol-eau, procede de preparation et utilisation pour isolement de l'orthohydroxymandelate de sodium
KR980009231A (ko) * 1996-07-31 1998-04-30 이승웅 P-히드록시페닐글리신의 제조방법
FR2760745B1 (fr) * 1997-03-11 1999-05-28 Hoechst France Procede industriel de preparation en continu de l'orthohydroxymandelate de sodium
NL1010090C2 (nl) * 1998-09-15 2000-03-17 Gerard Kessels Sociedad Anonim Werkwijze voor de bereiding van 2- en 4-hydroxyamandelzuur.
EP1660432A2 (en) * 2003-09-05 2006-05-31 Teva Pharmaceutical Industries Limited A recycling process for preparing sertraline
TW200514826A (en) * 2003-09-19 2005-05-01 Kyung In Synthetic Corp Alpha-hydroxy-benzeneacetic acid derivatives, and compounds having two 5-membered lactone rings fused to central cyclohexa-1, 4-diene nucleus using the same, and uses of the compounds
KR20050029016A (ko) * 2003-09-19 2005-03-24 (주)경인양행 벤조디푸라논계 신규 화합물과 그것의 제조방법 및 그것을이용한 섬유의 염색 또는 인쇄 방법
KR100555624B1 (ko) 2004-08-26 2006-03-03 (주)경인양행 알파-히드록시 벤젠아세틱 엑시드 유도체, 그것에 기반한시클로 헥사-1,4-디엔 모체에 2 개의 5환 락톤링을 가진화합물, 및 그것의 용도
CN101417942B (zh) * 2007-10-26 2011-09-21 宝山钢铁股份有限公司 一种制备对羟基扁桃酸的方法
CN112812003A (zh) * 2021-01-12 2021-05-18 湖南复瑞生物医药技术有限责任公司 4-羟基扁桃酸的制备方法
CN114736118B (zh) * 2022-04-26 2023-05-09 重庆欣欣向荣精细化工有限公司 一种3-甲氧基-4-羟基扁桃酸分离及其高纯度产物制备方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE32558C (de) * J. N. GALLAND in Paris Neuerung an Apparaten zur Rektifikation und Destillation von Spiritus und anderen Flüssigkeiten
DE2040218A1 (de) * 1970-08-13 1972-02-17 Technochemie Gmbh Verfahren zur Herstellung von Mandelsaeure
US3725437A (en) * 1970-09-16 1973-04-03 Sankyo Chem Ind Ltd Process for the preparation of {60 -hydroxy-{62 -phenypropionic acid derivatives and alkalimetal-or ammonium salts thereof
DE2115551C3 (de) * 1971-03-31 1980-01-10 Haarmann & Reimer Gmbh, 3450 Holzminden Verfahren zur Herstellung von aromatischen Hydroxyaldehyden
JPS5224542B2 (hu) * 1973-12-19 1977-07-01
EP0003825B1 (de) * 1978-02-20 1981-02-11 Diamalt Aktiengesellschaft Verfahren zur Herstellung von 4-Hydroxyphenylessigsäure
BE867287A (fr) * 1978-05-19 1978-11-20 Ici Ltd Sel de metal alcalin de l'acide p-hydroxy-mandelique
FR2427322A1 (fr) * 1979-06-15 1979-12-28 Hoechst France Parahydroxymandelate de sodium racemique cristallise, son procede de preparation et son application a la preparation du paraformylphenolate de sodium cristallise

Also Published As

Publication number Publication date
ATE3408T1 (de) 1983-06-15
EP0024181A1 (en) 1981-02-25
HU182707B (en) 1984-03-28
NO810291L (no) 1981-02-19
JPS56500964A (hu) 1981-07-16
WO1981000404A1 (en) 1981-02-19
US4368334A (en) 1983-01-11
DE3063330D1 (en) 1983-07-07

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